DE69203911T2 - Antihistamine and non-sedating benzimidazole derivatives, process for their preparation and their use as medicines. - Google Patents

Abstract

The present invention relates to novel benzimidazole derivatives characterized in that they are of the general formula I, and their therapeutically acceptable salts, <IMAGE> I in which: R1 and R2, which are identical or different, represent a hydrogen or a halogen atom, a lower alkyl radical, a hydroxyl radical, an alkoxy radical, an alkyl carboxylate radical, or an aryl or substituted aryl radical, n may take the values 0 or 1, m may take the values 2 to 4, X, Y, Z and W, which are identical or different, and which may even form part of another aromatic or nonaromatic ring, represent a nitrogen atom or a carbon atom linked to a hydrogen or to a halogen atom, or to another alkyl, aryl, carboxyalkyl, carboxylic, hydroxyl, alkyl hydroxyl, sulphonic or alkylsulphonic radical.

Description

The present invention relates to new benzimidazole derivatives, a process for their preparation and their use as medicaments.

The compounds forming the subject of the present invention have the general formula (I)

wherein

n can have the values 0 or 1,

m can have the values 2 to 4,

X, Y, Z and W, which are the same or different, represent a nitrogen atom or a carbon atom which is bonded to a hydrogen atom, to a halogen atom or to an alkyl, carboxyl or alkyloxycarbonyl radical.

Benzimidazole derivatives with different biological activities are already known in the scientific literature, for example with analgesic and anti-inflammatory activity (Japan Kokai 75, 126, 682), with a gastro-antisecretory activity (EP 246 126 and EP 5129); with an antihistamine activity (J. Jilek et al., "Collect. Czech. Chem. Commun." 1988, 53, 870-883; US Patent 4 200 641; "Drugs of the Future", VII; 510-1, 1982; R. Iemura et al., "J. Med. Chem.", 1986, 29, 1178-1183; R. Iemura et al., "J. Heterocyclic. Chem.", 1987, 24, 21-37; and French patent application FR 2 665 161).

The compounds forming the subject of the present invention are new derivatives of benzimidazole, specifically 1-(2-ethoxyethyl)-2-[ω[ω(azol-1-yl)alkyl)hexahydro-1,4-diazepin-1-yl-alkyl]benzimidazole, which are referred to in the present application as 1-(2-ethoxyethyl)-2-[ω[ω(azol-1-yl)alkyl]homopiperazin-1-yl-alkyl]benzimidazole. It has been found that these new derivatives have very good antihistamine activity and that they have no side effects on the central nervous system.

The new derivatives of general formula (I) can be prepared according to the present invention by one of the following processes:

Procedure A

By reacting a compound of the general formula (IIa)

or also (IIb) wherein R₁, R₂ each represent a hydrogen atom and n and n have the meanings given above, and wherein A represents a halogen atom or an easily "leaving (separable) group" selected from tosyloxy or mesyloxy, with a compound of the general formula (III)

where X, Y, Z and W have the meanings given above.

The reaction is carried out in the presence of a suitable solvent, e.g. dimethyl sulphoxide, dimethylformamide, alcohols, aromatic or non-aromatic hydrocarbons, ethers such as dioxane or diphenyl ether or mixtures of these solvents. This reaction is conveniently carried out in the presence of a base, e.g. hydroxides, carbonates or bicarbonates of alkali metals or a mixture of these bases. Alkali metal hydrides can also be used. The most suitable temperatures vary between ambient temperature and the reflux temperature of the solvent and the reaction time is between 1 and 24 h.

Procedure B

By reacting a compound of the general formula (IIa), wherein A represents a -NH₂- radical, with 2,5-dimethoxytetrahydrofuran.

The reaction is carried out in the presence of a suitable solvent, e.g. acetic acid, water, alcohols, ketones or mixtures of these solvents. The most suitable temperatures vary between ambient temperature and the reflux temperature of the solvent and the reaction time is between a few minutes and 24 hours.

Procedure C

By reacting a compound of the general formula (IV)

wherein R₁, R₂ and n have the meanings given above, with a compound of the general formula (V)

wherein X, Y, Z, W and m have the meanings given above and B represents a halogen atom or a readily "leaving group" selected from tosyloxy or mesyloxy.

The reaction is carried out in the presence of a suitable solvent, e.g. dimethyl sulphoxide, dimethylformamide, alcohols, aromatic or non-aromatic hydrocarbons, ethers such as dioxane or diphenyl ether, or mixtures of these solvents. This reaction is conveniently carried out in the presence of a base, e.g. the hydroxides, carbonates or bicarbonates of alkali metals, or a mixture of these bases. The most suitable temperatures vary between ambient temperature and the reflux temperature of the solvent and the reaction time is between 1 and 24 hours.

The following examples describe the preparation of new derivatives according to the invention. The following examples are for illustrative purposes only and do not restrict the invention thereto.

Procedure A example 1 Preparation of 1-(2-ethoxyethyl)-2-1{4-[4-(pyrazol-1- yl)butylihomopiperazin-1-yl-methyl}benzimidazole a) 1-(2-ethoxyethyl)-2-(4-benzyl-1H-homoninerazin-1-yl- methyl)benzimidazole

To a suspension of 2.04 g (46.7 mmol) of NaH (55% in a mineral oil) is slowly added a solution of 13.6 g (42.5 mmol) of 1H-2-(4-benzyl-1H-homopiperazin-1-yl-methyl)benzimidazole in 20 ml of dimethylformamide (DMF). Heat to 60-70°C for 1 h, then add a solution of 5.1 g (46.7 mmol) of 1-chloro-2-ethoxyethane in 5 ml of DMF.

The mixture is left to stand under the same conditions for 5 hours with stirring. It is poured into water and extracted with ethyl acetate, it is washed with water, the organic phase is dried with Na₂SO₄, it is filtered and evaporated. The residual oil is purified on a silica chromatography column. By eluting with chloroform/methanol (99/1) 5.65 g (50%) of 1-(2-ethoxyethyl)-2-(4-benzyl-1H-homopiperazin-1-yl-methyl)benzimidazole are obtained and with chloroform/methanol (97/3) 4.3 g (32%) of the starting product which has not reacted are recovered.

1H-RMN (CDCl₃): δ 1.12 (t,3H); 1.79 (m,2H); 2.69 (m,8H); 3.41 (g,2H); 3.63 (s,2H); 3.76 (t,2H); 3.98 (s,2H); 4.55 (t,2H); 7.25 (m,8H); 7.7 (m,1H).

b) 1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole

A solution of 5.94 g (15.15 mmol) of 1-(2-ethoxyethyl)-2-(4-benzyl-1H-homopiperazin-1-yl-methyl)benzimidazole in 80 ml of 80% acetic acid is heated for 16 hours at 60ºC together with 4.02 g of Pd/C 5% (water content 50%) under a hydrogen atmosphere of 5 at. The mixture is filtered and evaporated to dryness. The residue is taken up in chloroform and washed with 20% NaOH. with water and dried with Na₂SO₄, filtered and evaporated. 3.65 g (80%) of 1-(2-ethoxyethyl)-2-(homopiperazin-1-yl-methyl)benzimidazole are obtained.

1H-RMN (CDCl₃): δ 1.12 (t,3H); 1.78 (m,2H); 2.28 (S widened1H); 2.74-3.05 (m,8H) ; 3.41 (q,2H) 3.76 (t,2H); 4.02 (s,2H); 4.56 (t,2H); 7.25 (m,3H); 7.7 (m,1H). IR(film): 3312, 1463, 1119, 744 cm-1

c) 1-(2-ethoxyethyl)-2-(8-methylaza-5-azoniaspiror[4,6]undecane)benzimidazole bromide

A mixture of 4 g (13.24 mmol) of 1-(2-ethoxyethyl)- 2-(homopiperazin-1-yl-methyl)benzimidazole, 3.29 g (15.23 mmol) of 1,4-dibromobutane and 2.5 g (18.1 mmol) of potassium carbonate in 40 ml of chloroform is heated under reflux for 16 h. It is cooled, filtered and evaporated. The residue is triturated in ethyl ether to give 5.6 g (97%) of a hygroscopic solid, which is used as such without further purification.

1H-RMN (CDCl₃): δ 1.06 (t,3H); 2.24 (m,6H); 2.96-3.51 (m,8H); 3.72-3.90 (m,8H); 4.15 (s,2H); 4.53 (t,2H); 7.30 (m,3H); 7.74 (m,1H).

d) 1-(2-ethoxyethyl)-2-{4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl-methyl}benzimidazole

A mixture of 3 g (6.86 mmol) of 1-(2-ethoxyethyl)- 2-(8-methylaza-5-azoniaspiro[4,6]undecane)benzimidazole bromide, 0.56 g (8.24 mmol) of pyrazole, 1.8 g (13 mmol) of potassium carbonate and 30 ml of dimethylformamide is heated under reflux for 16 h. It is cooled, filtered and the filtrate is evaporated to dryness. The reflux is resumed with chloroform and washed with water. The organic phase is dried with Na₂SO₄, filtered and evaporated. The resulting oil is purified on a silica chromatography column (eluent: chloroform/methanol (9/1)). This gives 1.40 g (48%) of 1-(2- ethoxyethyl)-2-(4-[4-(pyrazol-1-yl)butyl]homopiperazin-1- yl-methylibenzimidazole in the form of an oil.

The spectroscopic data for its identification are given in Tables 1 and 2.

Example 3 Preparation of 1-(2-ethoxyethyl)-2-{4-[4-(4,5-dichloro-2methylimidazol-1-yl)butyl]homopiperazin-1-yl-methyl}benzimidazole

The preparation is carried out in the same manner as indicated in Example 1, achieving a yield of 36%.

The spectroscopic data for their identification are given in Tables 1 and 2.

Example 5 Preparation of 1-(2-ethoxyethyl)-2-{4-[4-(4-carboxypyrazol-1-yl)butyl]homopiperazin-1-yl-benzimidazole a) 1-(2-ethoxyethyl)-2-(8-aza-5-azoniaspiro[4,6]undecane)benzimidazole bromide

The preparation is carried out according to the same procedure as given in Example 1c, whereby a yield of 97% is achieved.

1H-RMN (CDCl₃): δ 1.09 (t,3H); 1.9-2.4 (m,6H); 3.42 (g,2H); 3.82 (t,2H); 3.9-4.1 (m,12H); 4,26 (t,28); 7.20 (m,3H); 7.50 (m,1H).

b) 1-(2-ethoxyethyl)-2-{4-[4-(4-ethyloxycarbonylpyrazol- 1-yl)butyl]homopiperazin-1-yl}benzimidazole

The preparation is carried out according to the same procedure as in Example 1 d and the crude product is obtained, which is purified on a silica chromatography column (eluent: chloroform/methanol (95/5), yield 35%.

1H-RMN (CDCl₃): δ 1.13 (t,3H); 1.33 (t,3H); 1.93 (m,6H); 2.6 (t,2H); 2.8 (m,4H); 3.35-3.82 (m,8H); 4.07-4.4 (m,6H); 7.1-7.25 (m,3H); 7.5 (m,1H); 7.85 (s,2H).

The ester prepared above is hydrolyzed by treating a solution in ethanol with a 10% sodium hydroxide solution for 15 hours at ambient temperature. The alcohol is evaporated and the aqueous solution is neutralized with hydrochloric acid. It is evaporated to dryness and the acid is extracted from the residue by digestion with isopropanol, yield 87%, melting point (m.p.) > 300ºC.

The spectroscopic data for their identification are given in Tables 1 and 2.

Procedure B Example 2 Preparation of 1-(2-ethoxyethyl)-2-{4-[4-(pyrrol-1- yl)butyl]homopiperazin-1-yl)methyl}benzimidazole

A solution of 2.98 g (8 mmol) of 1-(2-ethoxyethyl)-2-{4-(4-aminobutyl)homopiperazin-1-yl-methyl}benzimidazole and 1.06 g (8 mmol) of 2,5-dimethoxytetrahydrofuran in 30 ml of acetic acid is heated under reflux for 25 min. It is cooled, poured into ice-water, neutralized with NAHCO3 and extracted with chloroform. It is dried with Na2SO4 and evaporated to dryness under vacuum. 3.2 g of the crude compound are thus obtained, which is purified on a silica chromatography column (eluent: chloroform/methanol (92/8)), yield 51%.

The spectroscopic data of the compound are the same as given in Example 2 of Method C.

Procedure C Example 2 Preparation of 1-(2-ethoxyethyl)-2-{4-[4-(pyrrol-1yl)butyl]homoninerazin-1-yl-methyl}benzimidazole.

A mixture of 2.42 g (8 mmol) of 1-(2-ethoxyethyl)-2-homopiperazin-1-yl-methyl)benzimidazole, 1.39 g (8.8 mmol) of 1-(4-chlorobutyl)pyrrole, 1.65 g (12 mmol) of potassium carbonate and 1.65 g (11 mmol) of sodium iodide in 40 ml of methyl ethyl ketone is heated to reflux for 16 h. cool, filter and evaporate the filtrate to dryness. Take up the residue in chloroform and wash with water, dry, filter and evaporate under vacuum. The resulting crude compound is purified on a silica chromatography column (eluent: chloroform/methanol (92/8)) to give 1.9 g (56%) of 1-(2-ethoxyethyl)-2-{4-[4-(pyrrol-1-yl)butyl]homopiperazin-1-yl-methyl}benzimidazole.

The spectroscopic data for their identification are given in Tables 1 and 2.

Example 4 Preparation of 1-(2-ethoxyethyl)-2-{4-[4-pyrazol-1- yl)butyl]homopiperazin-1-yl}benzimidazole

The preparation is carried out in exactly the same manner as in the previous example and the compound is obtained in a yield of 49%, the salt of which with maleic acid has a melting point of 102 to 105 °C. Table 1 Example No. Method IR (cm⊃min;¹) (Film) Maleate Table 2 Example No. (s widened 1H)

Pharmacological activity

The products according to the invention are powerful antihistamines, which are characterized by the fact that they are free from sedative effects, in contrast to most known antihistamines.

In vivo antihistamine activity

The antihistamine activity was studied by determining the protective effect against the mortality induced by the product 48/80 in a rat. This test was carried out according to the procedure described by C.J.E. Niemegeers et al. ("Arch. Int. Pharmacodyn.", 234, 164-176 (1978)). The products forming the subject of the present invention are administered to rats by the intraperitoneal route. 60 min later, the compound 48/80 (0.5 mg/kg, i.v.) is administered. The protective activity is defined as the survival rate of the rats 4 h after the i.v. injection of 48/80.

The activity of the products is studied at several doses in order to determine the dose that can protect 50% of the animals (DE-50).

The antihistamine activity of the product of Example 1 is then reported. This activity is compared with that of difenhidramine, a reference antihistamine. "In vivo" antihistamine activity: Protective effect against death induced by 48/80 Example No. Difenhidramine

Sedative effect: 1) Irwin test

In order to investigate the absence of sedative effect of the products forming the subject of the present invention, they were administered intraperitoneally to rats and the behaviour of the animals was observed according to the standards described in the test by S. Irwin ("Science", 136, 123-128 (1962)).

Below is the result obtained for the product of Example 1 in the two evaluations indicating the sedative effect:

- Pas.: passivity, sedation, prostration, quantitative rating between 0 and 3. The ratings are made 1, 2 and 3 hours after the treatment.

- Ataxia: Ataxia, changes in coordination during locomotion are assessed. They are scored between 0 and 3. The assessments are carried out 1, 2 and 3 hours after the treatment.

The results of the study of the sedative activity of the product of the invention of Example 1 are given below by way of example. This activity was compared with that of difenhidramine, the control antihistamine. This product shows a very low sedative activity, in contrast to difenhydramine, which proved toxic at the dose of 80 mg/kg, ip, due to the depressant effects of SNC. Sedative effect: 1) Irwin test Example No. Dose Effect Difenhidramine toxic

Sedative effect: 2) Potentiation of sleep time induced by pentobarbital

The study of the potentiation of sleep time attributable to pentobarbital was carried out according to the procedure described by LE Allen et al. ("Arz. Forsch." 24 (6), (1974)). The products studied were administered orally. 1 hour later, sodium pentobarbital (35 mg/kg, sc) was administered and the time the animals woke up was determined. Sleep time was measured using an animal comparison group that had only been treated with sodium petrobarbital.

To complete the studies demonstrating the absence of sedative effect of the products forming the subject of the present invention, this test compared the activity of one of the products (Example 1) with the control antihistamine, difenhidramine. The results of this test with Example 1 and difenhidramine are given below. It can be seen that difenhidramine significantly potentiates sleep time at a dose of 20 mg/kg, whereas the product of Example 1 does not potentiate the sleep time induced by pentobarbital even at a dose of 160 mg/kg, the maximum dose tested. Sedative effect: (2) Potentiation of sleep time induced by pentobarbital Example No. Dose (mg/kg), po) Potentiation of sleep time Difenhidramine not significant significant difference to the comparison group (p < 0.05)

A specific galenic form for derivatives according to the invention is given below as an example. Tablets Formulation per tablet Compound of Example Lactose Maize starch Microcrystalline cellulose Polyvinylpyrrolidone Sodium croscarmellose Colloidal silicon dioxide Magnesium stearate

Claims (1)

1. Benzimidazole derivatives, characterized in that they correspond to the general formula (I) wherein n can have the values 0 or l, m can have the values 2 to 4, X, Y, Z and W, which may be the same or different, represent a nitrogen atom or a carbon atom bonded to a hydrogen atom, to a halogen atom or to an alkyl, carboxyl or alkyloxycarbonyl radical, and their therapeutically acceptable salts. 2. Compounds of general formula (I) according to claim 1, selected from the following group: - 1-(2-ethoxyethyl)-2-[4-[4-(pyrazol-1-yl)butyl]hornopiperazin-1-yl-methyl]benzimidazole, - 1-(2-ethoxyethyl)-2-[4-[4-(pyrrol-1-yl)butyl] homopiperazin-1-yl-methyl) benzimidazole, - 1-(2-ethoxyethyl)-2-[4-[4-(4,5-dichloro-2-methylimidazol-1-yl) butyl]homopiperazin-1-yl-methyl]benzimidazole, - 1-(2-ethoxyethyl)-2-[4-[4-(pyrazol-1-yl)butyl]homopiperazin-1-yl]benzimidazole, - 1-(2-ethoxyethyl)-2-[4-[4-(4-carboxypyrazol-1- yl)butyl]homopiperazin-1-yl]benzimidazole, - 1-(2-ethoxyethyl)-2-[4-[4-(4-ethyloxycarbonylpyrazol]-1-yl)butyl]homopiperazin-1-yl)benzimidazole. Process for preparing the compounds according to one of claims 1 and 2, characterized in that at least one of the following reactions is carried out: 3a) Reaction of a compound of general formula (IIa) or (IIb) wherein R₁ and R₂ each represent a hydrogen atom and n and m have the meanings given in claim 1 and A represents a halogen atom or an easily "leaving group" selected from tosyloxy or mesyloxy, with a compound of the general formula (III) wherein X, Y, Z and W have the meanings given in claim 1; 3b) reaction of a compound of the general formula (IIA), in which A represents a -NH₂- radical, with 2,5-dimethoxytetrahydrofuran; 3c) Conversion of a compound of general formula (IV) wherein R₁, R₂ and n have the meanings given above, with a compound of the general formula (V) wherein X, Y, Z, W and m have the meanings given above and B represents a halogen atom or a readily "leaving (splitting) group" selected from tosyloxy or mesyloxy. 4. Derivatives of general formula (I) and their therapeutically acceptable salts according to claims 1 and 2, in particular as medicaments used as antihistamines. 5. Pharmaceutical compositions, characterized in that they contain, in addition to a pharmaceutically acceptable carrier, at least one derivative of the general formula (I) or one of its physiologically acceptable salts according to one of claims 1 and 2. 6. Use of the derivatives of the general formula (I) and their physiologically acceptable salts according to one of claims 1 and 2 for the preparation of medicaments for the prophylaxis and for the treatment of various allergic diseases caused by histamine.